U.S. patent application number 10/000977 was filed with the patent office on 2002-04-11 for implantable sensor and integrity tests therefor.
Invention is credited to Schulman, Joseph H., Shah, Rajiv.
Application Number | 20020042561 10/000977 |
Document ID | / |
Family ID | 25495035 |
Filed Date | 2002-04-11 |
United States Patent
Application |
20020042561 |
Kind Code |
A1 |
Schulman, Joseph H. ; et
al. |
April 11, 2002 |
Implantable sensor and integrity tests therefor
Abstract
An implantable sensor includes electronic circuitry for
automatically performing on a periodic basis, e.g., every 1 to 24
hours, specified integrity tests which verify proper operation of
the sensor.
Inventors: |
Schulman, Joseph H.; (Santa
Clarita, CA) ; Shah, Rajiv; (Rancho Palos Verdes,
CA) |
Correspondence
Address: |
Ted R. Rittmaster
FOLEY & LARDNER
Suite 3500
2029 Century Park East
Los Angeles
CA
90067-3021
US
|
Family ID: |
25495035 |
Appl. No.: |
10/000977 |
Filed: |
November 30, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10000977 |
Nov 30, 2001 |
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09360343 |
Jul 22, 1999 |
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09360343 |
Jul 22, 1999 |
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08954171 |
Oct 20, 1997 |
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Current U.S.
Class: |
600/345 ;
327/104; 363/123 |
Current CPC
Class: |
A61B 5/14532
20130101 |
Class at
Publication: |
600/345 ;
327/104; 363/123 |
International
Class: |
A61B 005/05; H02M
007/00 |
Claims
What is claimed is:
1. In an electrochemical sensor having an hermetically sealed
portion and a non-hermetically sealed portion, the hermetically
sealed portion containing electronic circuitry, the
non-hermetically sealed portion having at least one electrode
associated therewith, the electronic circuitry comprising means for
measuring a specified parameter within body fluids or tissue to
which the at least one electrode is exposed, and means for
performing at least one integrity test to verify proper operation
of the sensor.
2. The electrochemical sensor of claim 1 wherein said means for
performing at least one integrity test comprises means for
automatically performing the at least one integrity test upon
occurrence of a specified event.
3. The electrochemical sensor of claim 2 wherein the specified
event comprises the passage of time in accordance with a predefined
schedule, whereby the at least one integrity test is automatically
performed in accordance with the predefined schedule.
4. The electrochemical sensor of claim 2-wherein the specified
event comprises the measurement of a parameter that falls outside
of predefined limits, whereby the at least one integrity test is
automatically performed whenever a parameter measurement indicates
the parameter is not within the predefined limits.
5. The electrochemical sensor of claim 2 wherein said at least one
integrity test comprises performing an electrical measurement
between the at least one electrode and another reference point
within said sensor.
6. The electrochemcial sensor of claim 2 wherein the electrical
measurement performed by the at least one integrity test comprises
making an impedance measurement between the at least one electrode
and reference point.
7. The electrochemical sensor of claim 1 wherein said sensor
comprises an implantable glucose sensor having a plurality of
electrodes associated with its non-hermetically sealed portion,
wherein said plurality of electrodes comprise a first working
electrode, a second working electrode, a reference electrode and a
counter electrode.
8. The electrochemical sensor of claim 7 wherein the at least one
integrity test comprises measuring the resistance between the first
working electrode and second working electrode, and wherein said
resistance measurement should be approximately 1000 ohms .+-.50%
when the sensor is functioning properly within its implantable
environment.
9. The electrochemical sensor of claim 7 wherein the at least one
integrity-test comprises measuring the voltage potential between
the reference electrode and the counter electrode and determining
if such voltage potential has changed more than about 40% since a
previous measurement of the voltage potential.
10. The electrochemical sensor of claim-7 wherein said at least one
integrity test comprises mesuring an electrical current that flows
between one of the first or second working electrodes and the
counter electrode while maintaining the reference electrode at
first and second reference potentials, thereby obtaining two points
on a voltage-current curve, and determining if the slope of the
voltage-current curve is within a prescribed degree of
flatness.
11. The electrochemical sensor of claim 10 wherein the first and
second reference potentials at which the reference electrode is
maintained are centered about 0.5 volts, wtih the first reference
potential comprising 0.5 volts minus Vx, and the second reference
potential comprising 0.5 volts plus Vx, where Vx is a voltage
ranging from about 0.05 volts to 0.20 volts.
12. The electrochemical sensor of claim 1 wherein at least three of
said electrochemical sensors are implanted within the same body
fluids or tissue location in close proximity to each other, and
wherein said at least one integrity test comprises independently
measuring the specified parameter with each of said implantable
sensors and comparing the results of said independent measurements
to determine if all of the measurements are within about 20% of
each other.
13. An implantable sensor comprising: implantable structure; means
integral with said implantable structure for generating an
electrical signal indicative of a monitored parameter; and
electronic circuitry integral with said implantable structure, said
electronic circuitry including means for automatically performing
on a periodic basis at least one specified integrity test which
verifies proper operation of the sensor.
14. The implantable sensor of claim 13 wherein said implantable
structure comprises an hermetically-sealed housing, an integrated
circuit (IC) chip inside of said housing, at least one electrode
external to said housing, and means for making an electrical
connection between the IC chip and said at least one electrode.
15. The implantable sensor of claim 14 wherein said means for
performing at least one specified integrity test comprises means
for measuring voltage, current, or impedance between said at least
one electrode and a specified reference point.
16. The implantable sensor of claim 15 wherein said specified
reference point comprises a point external to said
hermetically-sealed housing.
17. The implantable sensor of claim 15 wherein said specified
reference point comprises a point internal to said
hermetically-sealed housing.
18. A method of testing an implantable sensor, said sensor
including means for sensing a parameter and generating an output
signal indicative thereof, said method comprising the steps of:
placing circuitry integral with said sensor that performs at least
one integrity test designed to verify proper operation of said
implantable sensor; and periodically performing said at least one
integrity test while said implantable sensor remains implanted
19. The method of claim 18 further including implanting at least
three senors in the same general tissue area, and wherein said step
of periodically performing said at least one integrity test
comprises periodically monitoring said output signal from each of
said at least three sensors and checking to ensure that all three
output signals remain within a specified tolerance of each
other.
20. The method of claim 18 further including implanting at least
three senors in the same general tissue area, and wherein said step
of periodically performing said at least one integrity test
comprises periodically monitoring a voltage, current or impedance
measurement associated with each of said at least three sensors and
checking to ensure that all three measurements remain within a
specified tolerance of each other.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to implantable sensors, and
more particularly to monitoring such sensors for proper
performance. Even more particularly, the present invention relates
to integrity tests that are performed on a regular basis in order
to confirm proper sensor operation. A preferred sensor with which
the present invention may be used is an implantable glucose
sensor.
[0002] Implantable sensors are sensors adapted to be implanted
within living tissue, e.g., within a living patient. The patient
may comprise an animal or a human. Such implantable sensors are
typically used to monitor one or more physiological parameters
associated with the patient. For example, an implantable sensor may
monitor a patient's blood or other body fluids for the presence or
absence of a specific substance. Other implantable sensors may
monitor the patient's body temperature. While a preferred sensor
for use with the present invention comprises an implantable glucose
sensor, or groups of glucose sensors, it is to be understood that
the invention may be used with any type of implantable sensor(s).
It is also to be understood that the principles underlying
operation of an implantable sensor apply equally well to any sensor
that is to remain unattended and submerged or immersed within a
hostile environment, e.g., within a saline solution such as
seawater, for a prolonged period of time. Thus, although the
sensors described herein find particular applicability to sensors
adapted to be implanted within living tissue, and the description
is directed to such implantable sensors, the invention may also be
applied to remote sensors of any kind that must be immersed
unattended in a hostile environment for long periods of time.
[0003] In general, an implantable sensor may be used to provide
valuable data that assists in diagnosing or treating an illness, or
to help maintain or sustain a given level of physiological,
chemical, or other activity or inactivity. In the case of glucose
sensors, which are typically used with some type of
insulin-delivery system in order to treat diabetics, the glucose
sensors provide invaluable data needed to maintain the
concentration of glucose within the patient at an acceptable level.
Such glucose senors must perform properly; otherwise, false data
may be provided. Such false data (if acted upon) could result in
the administration of an inappropriate amount of insulin, leading
to death or serious injury. There is thus a critical need in the
art for a sensor which is reliable and which can be monitored for
proper function on a regular basis. Likewise, there is a need for a
glucose sensor which must work properly within certain specific
limits of accuracy.
SUMMARY OF THE INVENTION
[0004] The above and other needs are addressed by the present
invention which comprises an implantable sensor that includes
integral means for automatically performing a series of integrity
tests that test the sensor for proper performance, and which
thereby ensure that the sensor is correctly and accurately
performing its intended monitoring function(s).
[0005] In accordance with one embodiment of the invention, an
electrochemical sensor is provided that has an hermetically sealed
portion and a non-hermetically sealed portion. The hermetically
sealed portion contains electronic circuitry; and the
non-hermetically sealed portion has at least one electrode
associated therewith. The electronic circuitry includes means for
measuring a specified parameter within body fluids or tissue to
which the at least one electrode is exposed, and means for
performing at least one integrity test to verify proper operation
of the sensor. Preferably, the means for performing the integrity
test comprises means for automatically performing the integrity
test upon occurrence of a specified event, such as the passage of
time in accordance with a prescribed schedule (e.g., once every
hour, or once every day), or the sensing of a parameter that is out
of tolerance.
[0006] A preferred embodiment of the invention comprises an
implantable glucose sensor. Such glucose sensor includes, inter
alia, electronic circuitry for automatically performing on a
periodic basis, e.g., every 1 to 24 hours, specified integrity
tests which verify the proper operation of the glucose sensor. The
basic structure and operating characteristics of a preferred
implantable glucose sensor adapted for use with the present
invention are described generally in U.S. Pat. No. 5,497,772,
incorporated herein by reference. Important features and
enhancements of such sensor are further described in U.S. patent
application Ser. No. ______ (Attorney Docket No. 56287), filed Sep.
12, 1997; U.S. patent application Ser. No. 08/928,868 (Attorney
Docket No. 57794), filed Sep. 12, 1997; U.S. patent application
Ser. No. 08/928,871, filed Sep. 12, 1997 (Attorney Docket No.
57795); U.S. patent application Ser. No. ______ (Attorney Docket
No. 57721), filed concurrently herewith; and U.S. patent
application Ser. No. ______ (Attorney Docket No. 57726, filed
concurrently herewith; all of which are assigned to the same
assignee as the present application, and all of which patent
applications are also incorporated herein by reference.
[0007] The preferred glucose sensor is adapted for insertion into
the venous system of a patient where it is exposed to the patient's
blood, or into other areas of the patient where it is exposed to
other tissue or fluids of the patient. Once implanted, the sensor
produces electrical signals, i.e., an electrical current, that is
related to the sensed glucose concentration.
[0008] Most implantable sensors have one or more electrodes adapted
to contact the body tissue or fluids within which the sensor is
implanted. It is through such electrodes that the sensor is able to
sense the particular parameter it is designed to sense.
[0009] For example, as described in the above-referenced patent and
patent applications, the preferred glucose sensor includes several
electrodes, e.g., two working electrodes (W1 and W2), at least one
reference electrode (REF1), and a counter electrode (CNTR). Some of
the electrodes, e.g., the working electrodes and the counter
electrode, are made or coated from platinum, while the reference
electrode is typically made from or coated with silver chloride.
Some of the electrodes are surrounded by a prescribed enzyme,
typically in the form of a gel. A preferred enzyme used for this
purpose is glucose oxidase (referred to herein as "GOX"). All of
the electrodes are further submersed in a suitable conductive
fluid, e.g., a saline solution.
[0010] The electrodes of the preferred glucose sensor are typically
formed on one side of a substrate, with membranes being formed to
confine the conductive fluid and/or GOX in the areas needed to
expose the electrodes. On the other side of the substrate,
electronic circuitry is formed that connects the electrodes
appropriately so that the desired electrochemical activity can be
monitored and used as a measure of the concentration of glucose to
which the sensor is exposed. Such circuitry includes not only
circuits that monitor the sensed glucose concentration (which is
done, as explained below, by monitoring the current flow between
the electrodes, which provides a measure of the oxygen
concentration, which oxygen concentration in the presence of an
enzyme is inversely proportional to the concentration of glucose),
but also includes data processing circuitry to preliminary process
the sensed data (e.g., the measured current) and transmit it over a
two-line connection cable with a controller circuit to which the
sensor is connected. The circuitry is hermetically sealed, and
non-exposed portions of the electrodes are similarly sealed under a
coating of aluminum oxide or alumina or other suitable insulator.
Portions of the sensor are also insulated in epoxy. In a preferred
embodiment, several, e.g., three, such sensors may be daisy-chained
together, each operating independently of the others, yet each
being in close proximity with the others so that measured data from
different ones of the sensors can be compared.
[0011] In order for the sensor to perform its intended function, it
is important that the electrodes and circuitry all operate as
designed, and that the various insulative material or coatings used
with the sensor, e.g., alumina, zerconia, wax and/or epoxy, provide
the needed insulation and/or sealing properties.
[0012] In accordance with one aspect of the invention, special test
circuitry is provided as part of the sensor circuitry to
periodically check the integrity of the critical sensor functions
and/or parameters. When necessary or desired, the results of the
integrity tests are then reported by generating appropriate data
signals that provide an indication of the results of such integrity
tests, e.g., that warn when a given test has failed, and/or that
provide test data from which a quantitative measure of the test
results can be obtained.
[0013] In a preferred configuration, a plurality of sensors, e.g.,
three sensors, are daisy-chained together and implanted within a
patient in the same general area, i.e., in the same tissue or body
fluids. Each sensor operates independently of the others. If all
the sensors are functioning properly, then the output data obtained
from each sensor should be approximately the same. The data sensed
by each sensor may thus be used as a crosscheck against the data
sensed by the other sensors. In a similar manner, the information
obtained from the periodic integrity tests may be regularly
compared and checked with the corresponding integrity test
information obtained from the other sensors of the same group of
chained-together sensors. In this manner, the overall integrity of
the integrity tests is itself checked periodically.
[0014] It is thus an object of the invention to provide, within an
implantable sensor, e.g., of the general type disclosed in U.S.
Pat. No. 5,497,772, or a similar implantable electrochemical
sensor, a means for automatically verifying the integrity of the
sensor on a periodic basis.
[0015] It is a feature of the invention to provide
electrical/electronic circuits included as part of the sensor
circuitry that carry out a series of integrity tests on the sensor
on a scheduled basis, and that report the results of such tests by
way of test data that can be monitored over time and/or compared
with similar test data obtained from other implanted sensors.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The above and other aspects, features and advantages of the
present invention will be more apparent from the following more
particular description thereof, presented in conjunction with the
following drawings and Appendix wherein:
[0017] FIG. 1 shows a plurality of sensors implanted within body
tissue and/or fluids connected to a sensor controller;
[0018] FIG. 2A is an electrical diagram of a simplified glucose
sensor;
[0019] FIG. 2B is a graph that qualitatively depicts the
relationship between electrical current delivered to the electrodes
of the glucose sensor of FIG. 2A and the voltage applied between
the electrodes, and how such relationship varies as a function of
oxygen content;
[0020] FIG. 2C is a graph that qualitatively depicts the
approximately linear relationship that exists at a fixed electrode
voltage between the electrical current passing through the
electrode of the glucose sensor of FIG. 2A and the oxygen
concentration;
[0021] FIG. 3 shows an electrical schematic diagram that depicts
the use of two working electrodes within a glucose sensor, one to
provide a measure of the oxygen that reacts with the glucose in the
blood (and thereby provides a measure of the glucose in the blood),
and another to provide a reference baseline measurement of the
background blood oxygen concentration (which measurement is used
for compensation);
[0022] FIG. 4A depicts a partial exploded view of a glucose sensor
of a type with which the present invention may be used;
[0023] FIG. 4B depicts a sectional end view of the sensor of FIG.
4A;
[0024] FIG. 4C shows a bottom view of the sensor of FIG. 4A;
[0025] FIG. 4D is a block diagram that illustrates the manner in
which several, e.g., three, glucose sensors may be daisy chained
together and connected to a controller;
[0026] FIG. 5 conceptually illustrates the various components of
the glucose sensor and their interrelationship relative to
integrity tests that may be performed by the present invention;
[0027] FIG. 6 is a block diagram of the circuits included within
the sensor that are used to perform the integrity tests of the
invention;
[0028] FIG. 7 is a flow diagram that depicts one manner in which
the preferred sensor makes a glucose measurement; and
[0029] FIGS. 8A, 8B and 8C are representative calibration curves
that are used in carrying out the measurement method illustrated in
FIG. 7.
[0030] Appendix A illustrates various glucose calibration
algorithms that may be used as part of the present invention.
[0031] Corresponding reference characters indicate corresponding
components throughout the several views of the drawings.
DETAILED DESCRIPTION OF THE INVENTION
[0032] The following description is of the best mode presently
contemplated for carrying out the invention. This description is
not to be taken in a limiting sense, but is made merely for the
purpose of describing the general principles of the invention. The
scope of the invention should be determined with reference to the
claims.
[0033] Turning first to FIG. 1, there is shown a schematic diagram
of a plurality of implantable sensors 10a, . . . 10n, implanted
within body fluids or tissue 12 or other desired area. The sensors
10 may comprise any type of implantable sensor, e.g., a temperature
sensor, an oxygen sensor, a CO.sub.2 sensor, a glucose sensor, a pH
sensor, a salinity sensor, or the like. Each sensor 10 typically
includes at least one electrode 14 adapted to interact with or
sense some prescribed substance that may be present within (or
absent from) the tissue 12 to varying degrees. To this end, each
sensor 10 operates independently of the other sensors being used,
yet each is implanted within the same general area of the tissue or
fluids 12.
[0034] It is noted that some types of sensors, e.g, a temperature
sensor or an activity (motion) sensor, need not necessarily have an
electrode 14 that is exposed to the tissue or fluids 12 in order to
perform their sensing function. For purposes of the broad aspects
of the present invention, it will thus be appreciated that what is
important is not whether the sensor has one or more electrodes, but
rather that the sensor be capable of accurately sensing a parameter
of interest, and that the integrity of such sensing be regularly
checked or verified.
[0035] The sensors 10 are connected to a sensor controller 16 by
way of a suitable coupling cable 18. The controller 16 may or may
not be implantable. If the controller 16 is not implanted, then
appropriate means are employed, as is known in the art, along the
length of the cable 18 to transcutaneously interface with implanted
sensors 10 so that appropriate signal communication may take place
between the implanted sensors 10 and the controller 16. A common
transcutaneous interface technique known in the art is inductive
coupling, using both implanted and external coils. Alternatively,
optical, magnetic, or other types of signal transmission could be
used to achieve a transcutaneous signal link through the cable
18.
[0036] In accordance with the present invention, integrity tests
are performed at specified intervals, e.g., periodically, at least
once every 1-24 hours, or at other specified intervals, such as
whenever a measured parameter is out of tolerance, that check the
performance and basic operation of the sensors 10. This is done to
safeguard the patient from a malfunctioning sensor, which
(depending upon the function of the sensor) could prove very
dangerous to the patient. Alternatively, where the sensors are
implanted or positioned in a remote, inaccessible area, e.g., deep
in the ocean or within a sealed saline solution over a long period
of time, such integrity tests, performed at specified intervals,
provide confidence in the data produced by the sensors.
[0037] The integrity tests may be initiated from the controller 16,
or may be initiated from circuitry that forms an integral part of
the sensor 10. When the integrity tests are performed, the results
of such tests are transmitted to the controller 16, where the
controller analyzes such results and/or makes the results available
(e.g., through an appropriate telecommunicative link, such as an
inductive, magnetic, rf, or optical link) to an external or other
device (such as an external programmer) adapted to display or
communicate the test results to the patient, medical personnel, or
others who are monitoring the test data. The use of external
programmers to interface with implantable devices is well known in
the art, as evident from, e.g., U.S. Pat. No. 5,609,606,
incorporated herein by reference.
[0038] Various types and kinds of integrity tests may be performed
in connection with the sensors 10 in accordance with the present
invention. One basic integrity test that may be made involves
monitoring the sensor output signal, i.e., that signal which
provides a measure of whatever it is that the sensor is measuring,
from each of a plurality of sensors located within the same general
tissue area, to see if there is a consensus between such
measurements. That is, assume there are five identical sensors all
implanted within the same general tissue area, and all configured
to measure the same substance within that tissue area. If all five
sensors provide approximately the same measurement data, e.g.,
within about 20% of each other, then that indicates--i.e., provides
integrity test data--that all five sensors are performing properly.
Should four of the sensors agree, and one disagree, then that
indicates the disagreeing sensor is likely malfunctioning. As a
result of such finding, all sensor data subsequently obtained from
such malfunctioning sensor may be ignored, or alternatively the
sensor may be disabled.
[0039] In a similar manner, if three sensors are used, a periodic
or other scheduled or triggered check of the output signal from all
three sensors may reveal agreement (consensus) or lack thereof. If
there is agreement, then all sensors are presumed to be operating
correctly. If two sensors agree, but one does not, then the one
that does not agree is likely not functioning properly. If all
three sensors disagree, then that could trigger a need for
recalibration, or other appropriate step, to determine which sensor
is functioning properly.
[0040] Other types of integrity tests that may be performed,
depending upon the capabilities of the sensors 10, include
impedance (e.g., resistance) and/or voltage measurements, e.g.,
measuring the impedance and/or voltage from the electrode 14 of one
sensor 10a, to a reference electrode, e.g., at the controller 16
(if implanted), or at some other location. Alternatively, the
impedance and/or voltage may be measured between the electrode 14
of one sensor 10a and another sensor 10n.
[0041] As indicated, a preferred sensor 10 with which the present
invention may be used, is a glucose sensor 52 of the type that is
described in the above-referenced '772 U.S. patent, or the
above-reference patent applications. This preferred glucose sensor
52 is electrically depicted in FIG. 2A. Such sensor 52 is based on
the "enzyme electrode" principle wherein an enzyme reaction and an
electrochemical detector are utilized to measure the concentration
of glucose. More particularly, the sensor includes at least three
electrodes: a first working electrode W1, a collector electrode C,
and a reference electrode R, submersed in a suitable conductive
liquid 54, such as a saline solution of water (H.sub.2O), confined
by a first membrane 55. A fixed trim voltage V is applied between
the electrode R and the electrodes W1 and C. A suitable enzyme E is
immobilized in a second membrane 56 so as to surround the first
working electrode Wi. For a glucose sensor, the enzyme E is
preferably glucose oxidase (GO).
[0042] During operation, when the sensor is implanted in the
patient's tissue, e.g., blood, the enzyme E is exposed to the
glucose and oxygen present in the tissue. Both the glucose and
oxygen diffuse from the tissue into the membranes 55 and 56
whereat, in the presence of the enzyme E, they react to produce
gluconic acid and H.sub.2O.sub.2. The rate of the reaction is
directly related to the concentration of glucose in the tissue and
is monitored by an electrochemical oxygen detector made up of the
electrodes W1, R and C, a current source 58 and a voltage source 60
(FIG. 2A). The working electrode W1 and the counter electrode C are
preferably made or coated from platinum (Pt). The reference
electrode R is typically made form or coated with silver chloride.
When a trim voltage V is placed across the electrodes R and W1, as
well as across R and C, a current I tends to flow between the
electrodes C and W1. (Assuming the voltage source is an ideal
voltage source, with infinite impedance, no current flows through
the reference electrode R.) When the above chemical reaction
occurs, oxygen is consumed at the working electrode W1. The amount
of oxygen remaining can be determined as a function of the amount
of current flowing through the working electrode W1. More
particularly, it can be shown that the relationship between the
current (I) that flows and the trim voltage (V) varies as a
function of the oxygen concentration as shown qualitatively in FIG.
2B. For a high concentration of oxygen (O.sub.2), a curve 62
establishes the relationship between I and V. For a low
concentration of O.sub.2, a lower curve 64 establishes the
relationship between I and V. For each value of O.sub.2
concentration between the high concentration curve 62 and the low
concentration curve 64, another curve (intermediate the curves 62
and 64) establishes the current-voltage relationship, with each
curve of the family corresponding to a different O.sub.2
concentration.
[0043] To measure the O.sub.2 concentration using a circuit such as
is shown in FIG. 2A, all that need be done is to force the trim
voltage V to be affixed value V.sub.R, where V.sub.R typically
ranges between 0.3 and 0.7 volts, e.g., 0.5 volts. This is done by
adjusting the current I until the desired trim voltage V.sub.R is
obtained. At the voltage V.sub.R, the relationship between the
current I and the oxygen O.sub.2 is substantially linear, as
depicted qualitatively in FIG. 2C. Thus, using a sensor such as is
functionally depicted in FIG. 2A, the amount of oxygen remaining at
the working electrode W1 is simply a function of the current I
required to force the trim voltage V to V.sub.R.
[0044] Since the oxygen detector is monitoring the oxygen not
consumed by the enzyme reaction, the detector signal, i.e., the
current I, is inversely related to the glucose concentration. The
more glucose in the tissue, e.g., the blood, the less oxygen will
be detected by the oxygen detector with the enzyme present.
[0045] To improve the accuracy of the oxygen determination made by
the detector of FIG. 2A, and in particular to allow compensation
for changes in the background blood or tissue oxygen concentration,
a second working electrode W2 is employed at a location in the
sensor that is not surrounded by the enzyme E, as shown in FIG. 3.
As such, the electrode W2 simply detects background oxygen
concentration (not oxygen consumed by the enzyme reaction), and
thus provides a means of compensating the oxygen measurement made
using the first working electrode W1 for background oxygen.
[0046] As seen in FIG. 3, a first adjustable current source is
realized from an operational amplifier 68 and a feedback loop 70. A
second adjustable current source is likewise realized form an
operational amplifier 72 and a feedback loop 74. Both the first and
second current sources apply their respective currents to the
collector electrode C. A measurement of the current I1 flowing
through the first working electrode W1 is provided by current
sensing element 71. Similarly, a measurement of the current I2
flowing through the second working electrode W2 is provided by
current sensing element 75.
[0047] In operation, the trim voltage V is set to the desired fixed
trim value V.sub.R, and the currents II and 12 are measured. The
current I1 provides a measure of the oxygen remaining at the
working electrode W1, which in turn provides an inverse measure of
the glucose concentration in the blood or other tissue. The current
I2 provides a measure of the background oxygen in the blood or
tissue, and thus provides a means for compensating the I1
measurement for background oxygen variations. The absolute
quantitative value of the glucose level is determined by comparison
of the two detector signals, i.e., the two currents, I1 and I2, and
by reference to a previously determined calibration. The basic
calibration technique is described below in conjunction with the
flow chart of FIG. 7 and the calibration curves of FIGS. 8A, 8B and
8C. More detailed information relative to the various calibration
algorithms that may be used are described in Appendix A.
Appropriate processing to obtain such quantitative measure of the
glucose concentration is performed by appropriate processing
circuits, typically included within the controller 16 or an
external programmer.
[0048] Turning next to FIGS. 4A, 4B, 4C and 4D, additional details
are provided concerning the preferred manner of making a sensor 10
in accordance with the invention. Further details may be found in
the patent applications referenced above. Basically, the sensor
includes a substrate 100 on which an integrated circuit (IC) chip
102 is mounted and connected to selected other electrical
components, such as a capacitor 104, via conductive traces that are
deposited or etched on the surface of the chip 100. A suitable
cover 106 fits over the electrical components 102, 104, and
connective traces, and is hermetically sealed to the substrate 100
so as to form an hermetically sealed portion of the sensor 10.
Electrical contact with the circuits and components within the
hermetically sealed portion is made via pads 108 and 110 and 109
and 111 located on respective ends of the substrate 100. These pads
have conductive traces connected thereto that tunnel into the
hermetically sealed portion through the ceramic substrate, in the
manner taught in U.S. patent application Ser. No. 08/515,559, filed
Aug. 16, 1995, incorporated herein by reference. Essentially, these
traces pass vertically down into the substrate 100, then
horizontally across the substrate to a point underneath the
hermetically sealed portion, and then vertically back up into the
hermetically sealed portion.
[0049] In a similar manner, conductive traces pass through the
substrate 100 from the IC chip side of the substrate to an
electrode side 112 of the substrate, which (as drawn in FIG. 4B) is
the underneath or bottom side of the substrate 100. Each of the
traces that pass through the substrate from the IC side to the
electrode side do so in a stair-step manner, as illustrated in FIG.
4B by the trace 114, so as to preserve the seal of the hermetic
portion. That is, there are no traces that tunnel through the
substrate which do so in a single vertical or straight segment.
Rather, there is always at least onea vertical segment connected to
at least one horizontal segment, as taught in the above-referenced
patent application (Ser. No. 08/515,559). In this manner, the
stair-step tunneling traces 114 function as electrical feedthroughs
into the hermetically sealed portion of the sensor.
[0050] On the electrode side 112 of the substrate 100, a plurality
of electrodes are arranged in a suitable pattern, as illustrated in
FIG. 4C. These electrodes may include, e.g., a first working
electrode W1, a second working electrode W2, a counter electroce
CNTR, a first reference electrode REF1, a second reference
electrode REF2, and a platinum black electrode Pt, and may be
arranged in various patterns. As taught in the '772 patent and the
above-reference patent applications, these electrodes are all
electrically insulated from each other by placing a layer of
insulation, such as alumina, between the electrodes. A thin inner
sheath of silicone rubber then covers the substrate electrodes, and
includes a thin pocket or space above the electrodes wherein a
suitable conductive fluid, such as PHEMA, is maintained. This thin
inner sheath is covered by a much thicker sheath 116, also made of
silicone rubber or an equivalent material. A pocket, or window, is
formed within this seath 116 above the working electrode W1,
wherein the GOX is placed.
[0051] For purposes of the present invention, the important feature
of the sensor 10 is that each of the plurality of electrodes on the
electrode side (which comprises the non-hermetic portion of the
sensor) of the substrate 100 are electrically connected with the
hermetically-sealed circuitry on the IC side of the substrate
100.
[0052] A preferred arrangement of the sensors 10 is to connect a
plurality of such sensors in a daisy chain, as depicted in FIG. 4D.
In FIG. 4D, three sensors 10a, 10b and 10c are thus connected in
series, although this is only exemplary. Any number of sensors
could be connected in this manner. Advantageously, the pads 108,
110, 109, 111 associated with each sensor, facilitate such
daisy-chain connection. Moreover, as described in the
above-referenced patent application, Ser. No. ______, (Attorney
Docket No. 56287) such connection may be effectuated using just two
conductors 118 and 120, yet control commands and data may still be
readily transferred between the sensors 10a, 10b and 10c and/or a
controller 16. It is noted that the two conductors 118 and 120 are
insulated conductors, and that at the point where they bond with
the pads 108 and 110, or 109 and 111, they are covered with epoxy,
or other suitable insulator, but such covering does not create an
hermetic seal. That is, there will be some leakage to the pads
108-111. However, as explained in the above reference patent
application, that is one of the advantages of the present
sensor--its ability to function even in a leaky or noisy
environment.
[0053] Turning next to FIG. 5, there is shown a schematic
representation of the preferred sensor 10, including the various
electrodes located on the non-hermeitcally sealed portion on the
electrode side 112 of the substrate 100, and the IC chip 102
located on the hermetically sealed portion of the substrate 100
(the other side of the substrate 100), and the stair-step
feedthrough connections 114 that electrically connect the two
portions to each other. The IC chip 102 may include various types
of circuits for processing and handling measured signals obtained
via the electrodes or otherwise generated or sensed within the
sensor 10, and/or for decoding and responding to various commands
received through the connections 108, 110 from a controller 16. The
types of circuits that are used in connection with a preferred
glucose sensor are fully described in the previously referenced
patent applications. These circuits include, e.g., a line interface
circuit, a low power rectifier circuit, a current-to-frequency
converter circuit, multiplexer circuits, decoder/encoder circuits,
and the like.
[0054] For purposes of the present invention, however, the types of
circuits that need be included within the IC chip 102, or otherwise
available within the sensor 10, are shown in the block diagram of
FIG. 6. It is recognized that these circuits, as shown in FIG. 6,
may not represent all the circuits that may be included within-the
sensor 10. This is because the types of circuits used with the
sensor 10 will be a function of what kind of sensor the sensor 10
is. For purposes of the present invention, however, it does not
matter what type of sensor the sensor 10 is. All that matters is
that the sensor include some means of checking its own performance,
e.g., some means for performing one or more integrity tests, and
then communicating the results of such test to a user or otherwise
using the results to confirm proper operation of the sensor. Hence,
all that is shown in FIG. 6 are those kinds of circuits that would
most likely be needed in order to practice the integrity tests of
the present invention. It is noted that in the preferred
implantable glucose sensor, as described, e.g., in the
above-reference patents and patent applications, that circuits are
included on-board the sensor chip, in one form or another, which
allow the measurement functions described in connection with FIG. 6
to be carried out.
[0055] In FIG. 6, the dotted line 122 represents the boundaries of
the hermetically sealed portion of the sensor. Not included within
the hermetically sealed portion 122 are a plurality of electrodes
W1, CNTR, W2 and REF1, and connection pads 108, 110, connected to
conductive leads 118 and 120. The number and types of electrodes is
exemplary. For purposes of the present invention, there will
typically be at least one electrode not included within the
hermetically-sealed portion 122, and there could be more electrodes
than is shown in FIG. 6.
[0056] The circuits included within the hermetically sealed portion
122 include a multiplexer (MUX) 124 that selectively connects any
two of the electrodes external to the hermetically-sealed portion
or any additional sensing element 126 or reference points 110, 128
within the hermetically-sealed portion to two measurement points
130A and 130B. A current measurement device 132 (e.g., a current
meter), a voltage measurement device 134 (e.g., a voltage meter),
and a variable voltage source 136 may then be selectively connected
to the measurement points 130A and 130B through a connection matrix
131. That is, with the connection matrix 131, the voltage between
any two reference points, e.g., between any two electrodes selected
by the MUX 124, and/or the current flowing between any two
reference points selected by the MUX 124, while a specified
potential is applied between the selected reference points, may be
measured.
[0057] The measurement circuits shown in FIG. 6 are controlled by a
control circuit 138. The control circuit, in turn, receives
commands from, or sends data to, a decoder/encoder circuit 140. The
decoder/encoder 140 is coupled to the input lines 118 and 120
(which are connected to a suitable controller 16--see FIG. 1 or
FIG. 4D) through an interface circuit 142. All of these circuits
may be as described in the previously-referenced patent
applications, or may be of any other suitable design. None of these
circuits, per se, comprise the present invention. Rather, they are
simply exemplary tools that may be used to help carry out the
invention.
[0058] The on-board control circuit 138 may be, for example, a
microprocessor circuit, including memory circuits for storing an
operating program that controls which integrity tests are performed
and in what sequence. Alternatively, the control circuit 138 may be
a simple state machine, controlled by command signals received from
the external controller 16, in which case control of the integrity
tests can be made from the external controller 16.
[0059] With reference now to both FIGS. 5 and 6, the integrity
tests that may be performed as part of the present invention will
be described. In general, such tests include measuring the voltage
and/or current that flows between any two points, which two points
may comprise two external points (not within the hermetically
sealed portion 122), or an external point and an internal point,
such as the reference point 128 (which may comprise, e.g, a ground
or common reference point). With such voltage and/or current
measurements, the impedance (resistance) between the selected two
points, e.g., electrodes, can be determined. The impedance
measurements, in turn, provide valuable information regarding
whether the sensor 10 is functioning properly. Moreover, by
changing the voltage potential that is applied between the two
points being monitored, various operating points of the circuitry
within the sensor IC chip 102 may be obtained and analyzed, thereby
confirming, e.g., that the circuits are operating in accordance
with a desired design. For example, for the preferred glucose
sensor, the basic operating curves shown in FIG. 2B may be
confirmed, thereby confirming the accuracy of the measurement
relationship shown in FIG. 2C.
[0060] In addition to current, voltage, and impedance measurements,
other important measurements can also be made. For example, the
internal sensor 126 may comprise, in one embodiment, a temperature
sensor that provides an electrical signal indicative of the
temperature on the sensor chip. Simply conveying the temperature
measurement could serve as an integrity test because if the
temperature is out of an anticipated range, then that could provide
an indication that something is not working correctly within the
sensor. In another embodiment, the internal sensor 126 may comprise
an motion or activity sensor, so that if a signal was received that
did not agree with a known and anticipated pattern of motion or
activity, that too could serve as a valuable indicator of whether
the sensor is performing as designed. Still further, the reference
point 128, or another internal reference point, could be coupled to
the internal voltage source 136 so that the voltage potential of
such source could be measured. Again, being able to periodically or
regularly measure the voltage potential available within the sensor
could provide valuable information regarding whether the sensor is
performing as designed. Additionally, the reference point 128 may
be connected to the case of the sensor, or the case of the sensor
may itself comprise a reference electrode.
[0061] When the sensor 10 comprises the preferred glucose sensor,
the desirable sensor parameters to monitor may include:
[0062] (1) verifying the platinum electrode current stability for
oxygen monitoring, and for current sinking;
[0063] (2) checking the silver chloride to gel voltage
stability;
[0064] (3) checking the integrity of the gel pH;
[0065] (4) checking the electrical conductivity of the saline
solution;
[0066] (5) verifying the integrity of the aluminum oxide and/or
other, e.g., epoxy, insulation;
[0067] (6) determining the GOX activity level; and
[0068] (7) checking the accuracy of the oxygen sensor.
[0069] Advantageously, these sensor parameters can be monitored, on
a regular basis, e.g., one every 1-24 hours (or in accordance with
another desired schedule) as controlled by an on-board
microprocessor or equivalent control circuit (or by a
microprocessor or equivalent within the remote controller 16) by
performing the integrity tests described below.
[0070] First, the leakage current can be measured between e.g.,
between the outside body solution and an uninsulated platinum black
electrode or other reference point that is exposed to the body
solution. With reference to FIG. 5, for example, such measurement
could be made by measuring the resistance between the case cover
106 (connected through point 128 to the MUX 124, FIG. 6) and each
of the pads 108 and 110. Alternatively, an additional uninsulated
Pt.--Black electrode could be included on the substrate 100. When
performing such measurement, any signals being transmitted over the
coupling wires 118 and 120 would be stopped for a prescribed time
period T1, e.g., 100 msec, and the leakage current between the pads
108 or 110 and the case 106, or between pads 108 and 110 (or
between pads 109 and 111, FIG. 4A) could be measured. This leakage
current should be within a certain range, as a function of the
conductivity of the saline solution within which the sensor is
immersed and other factors. A typical value of leakage current
might be 100 .mu.A.
[0071] Next, the leakage between any of the electrodes, e.g., the
electrodes W1, W2, CNTR, REF1, REF2 and the conductors (pads 108,
110) may be measured. This measurement could also be measured
between any of the electrodes and the case, if the case is
connected or connectable to the measurement circuitry. This leakage
current should be very small, i.e., it should not exceed I.sub.0,
where I.sub.0 is on the order of 1 pA. If the leakage current does
exceed I.sub.0, i.e., if the measured leakage current is between
about 1 pA-1000 pA, then that indicates the sensor's performance is
borderline, and there could be a problem for statistical purposes.
If the measured leakage current is within the range of, e.g., 10
nA-1 .mu.A, then that means the sensor will provide erroneous
values.
[0072] Next, a resistance measurement may be made between any two
electrodes. For example, the resistance between the W1 and W2
electrodes effectively measures the resistance of the PHEMA (or
conductive solution that is confined to the region of these
electrodes). This resistance should be less than about 1000 ohms.
If the resistance is in the range of 10K-100K ohms, then that means
the sensor readings would not be accurate.
[0073] As a further integrity test, the flatness of the
current-voltage curve (see FIG. 2B) may be checked. This is done,
e.g., by measuring the current that flows between the W1 and W2
electrodes for at least two different reference voltages.
Preferably, three points are taken, a center reference voltage,
corresponding to V.sub.R in FIG. 2B, of, e.g., 0.5 volts is applied
and the current flow is measured. Then, the reference voltage is
varied .+-.0.1 volts, and additional currents are measured at each
point. From these measurements, the slope of the I-V curve can be
checked. It should be relatively flat, as qualitatively shown in
FIG. 2B. If the slope is <2%, then that is good. If the slope is
linear to zero, that is bad. That is, once the plateau shown in
FIG. 2B ceases to exist, the sensor is not able to perform its
oxygen-sensing function. As another criteria, the slope of the I-V
curve in its flat region may be measured when the sensor is first
manufactured. This initial slope value can then be saved as a
reference value. If a subsequent measurement of the slope is more
than 20% different than the reference value, then that indicates
the sensor is bad.
[0074] Another integrity test is to check the integrity of the
insulation layer that is used to separate the electrodes. As
explained above, this insulation layer is placed between the
electrodes, but does not cover these electrodes. The test may be
performed by placing a separate electrode, e.g., REF2, on the
electrode surface 112 and completely coating this electrode with
the insulation material, e.g., alumina Al.sub.2O.sub.3. Then, the
impedance between this covered electrode and any other electrode or
reference point can be measured. If the insulation layer is intact,
then this impedance should be very high, near infinite
impedance.
[0075] An additional integrity test is to measure the CNTR to REF1
potential. For a given O.sub.2 concentration level, the CNTR-REF1
voltage should be stable. No drift should be present. Thus, this
measurement should be taken several times in succession over a
relatively short time period (to assure the O.sub.2 level does not
significantly change) and these successive measurement values
should then be compared to each other. Any change more than about
.+-.20% would indicate that there is a problem with the sensor.
[0076] An important integrity test, as has previously been
mentioned, is to compare the measured O.sub.2 values from a
plurality of sensors, e.g., three sensors, that are implanted
within the same general tissue area. These measurements should all
agree with each other within an acceptable tolerance, e.g.,
.+-.10%. If there is disagreement, then appropriate decision steps
are taken to identify the erroneous sensor, e.g., majority rules.
If all sensors disagree, then recalibration is called for. As a
related integrity test, the calculated glucose concentration for
each of the plurality of sensors can also be compared.
[0077] Yet another integrity test that can be performed is to
measure the open circuit voltage between specified electrodes. For
example, an open circuit voltage can be measured between a separate
platinum black electrode and the reference electrode. With respect
to FIG. 5, this means measuring the open circuit voltage between
the Pt.-Black electrode and the REF1 electrode. This voltage should
be zero. Similarly, the open circuit voltage between the electrodes
W2 and CNTR can be measured. It, too, should be zero for 0 current
flow. Likewise, the open circuit voltage between W1-CNTR should be
zero for 0 current flow. A set voltage, e.g., V.sub.R, should exist
between W2-REF1 and W1-REF1.
[0078] In general, then, the integrity tests for the preferred
glucose sensor include current leakage tests, resistance tests,
voltage tests, and I-V characteristic tests (curve flatness).
Experience indicates that the results of these integrity tests,
e.g., the amount of leakage current that occurs, will start to
increase or significantly change from prior values before major
sensor problems occur. It is therefore important to perform these
integrity tests on a regular basis, e.g., once every day, while the
sensor is within the patient. A good time to perform the tests is
at night when the patient is sleeping and when the O.sub.2
concentration is stable.
[0079] Data communication between the implanted sensor and the
controller 16 may occur using any suitable type of modulation
scheme and/or carrier transmission system, as is known in the art.
One type of data transmission scheme is as disclosed in applicants
copending patent application, Ser. No. ______, filed Sep. 12, 1997
(Atty Docket No. 56287), previously incorporated herein by
reference.
[0080] The results of the sensor tests, if problematic, may be
communicated through the controller 16 (see FIG. 1) to appropriate
medical personnel. Preferably, an appropriate message is
communicated to the patient, as soon as the external programmer is
coupled to the system, or through other appropriate signaling or
communication means, to inform the patient that he/she should
contact his/her doctor or clinic as soon as is reasonably possible.
The patient need not be told the exact nature of the problem
identified by the integrity tests, only that he/she should contact
his medical doctor or clinic for evaluation. The doctor or other
medical personnel could then evaluate the data and make a
determination if a true problem exists, and if so, what type of
corrective actions if any, is needed.
[0081] One type of corrective action that may be needed, either on
an automatically-scheduled basis or as the need arises, is a
calibration or recalibration of the sensor(s). Appropriate
algorithms for calibrating or recalibration the preferred glucose
sensors are shown in Appendix A, incorporated herein by
reference.
[0082] Closely related to calibration of the sensor(s), where the
sensor(s) comprise a glucose sensor of the type disclosed in the
referenced patent applications, is the manner in which the glucose
concentration is determined using the sensor(s). The basic approach
for determining glucose concentration is illustrated in the flow
diagram of FIG. 7. As previously described, the glucose sensor
determines the amount of glucose present in the tissue being
monitored by measuring the amount of oxygen in the presence of a
prescribed enzyme. The sensor provides, as an output signal, an
electrical current. In the preferred embodiment, two electrical
currents are provided as the output signal of the sensor. A first
electrical current flows through the first working electrode W1
(the one which is surrounded by GOX, or other suitable enzyme) and
provides a measure of the oxygen at the first working electrode
(which oxygen amount is inversely related to the glucose that is
present). A second electrical current flows through the second
working electrode W2 and provides a measure of the background
oxygen present at the second electrode W2.
[0083] With reference to FIG. 7, it is seen the two currents used
to measure the glucose level may be designated as I.sub.W1(t) and
I.sub.N2(t). In FIG. 7, there currents are identified as "Input"
currents (even though they are also output currents from the
sensor), because they serve as the starting point, or "input", in
order to derive the glucose concentration.
[0084] As shown in FIG. 7, the second current, I.sub.W2(t), is
measured and the value is applied (see block 150 of FIG. 7) to an
appropriate conversion or transfer curve, e.g., of the type
illustrated in FIG. 2C or an equivalent (e.g., a look-up table
would serve the same function) in order to convert the measured
current to a measure of oxygen. An example conversion curve used
for this purpose is shown in FIG. 8A. For example, with reference
to FIG. 8A, if the current I.sub.W2(t) is 200 nA, then that
translates to a background oxygen concentration, PO.sub.2, of about
7.8%. This percent oxygen can then be converted, as required, to a
measure of the background oxygen concentration. CO.sub.2(t), by
knowing the volume and pressure associated with the sample size.
The units of the background oxygen concentration CO.sub.2(t) are
typically expressed in mg/dl at a specified pressure (mmHg).
[0085] Once the background oxygen concentration PO.sub.2 is
determined, this value may be used to compensate for the
measurement taken at the enzyme-surrounded electrode W1 see block
152 of FIG. 7). To achieve this compensation, the value of PO.sub.2
from FIG. 8A is taken to a second transfer curve, e.g., as shown in
FIG. 8B, to determine a corresponding first current value,
I.sub.W1(t.sub.GLUCOSE=0). For example, if PO.sub.2 is 7.8%, then
from FIG. 8B it is seen that I.sub.w1(t.sub.GLUCOSE=0) is about 180
nA.
[0086] A ratio of the two current values, the determined
I.sub.W1(t.sub.GLUCOSE=0) and the measured I.sub.W1(t), is next
determined (block 154 of FIG. 7). By way of example, if I.sub.W1(t)
is measured to be 150 nA (I.sub.W1(t) should always be less than
I.sub.W1(t.sub.GLUCOSE=0)) then the ratio of I.sub.W1(t) to
I.sub.W1(t.sub.GLUCOSE=0) would be 150/180=0.833. This ratio is
then applied (see block 156 of FIG. 7), to a glucose sensor
calibration curve, as shown in FIG. 8C. From such glucose
calibration curve it is seen that the ratio of glucose
concentration to oxygen concentration, C.sub.g(t)/C.sub.o(t), is
about 2.7 mg/dl/mmHg. The previouslydetermined background oxygen
concentration, CO.sub.2(t), is then multiplied by this ratio (block
158) in order to calculate the measured glucose concentration,
C.sub.g(t).
[0087] As described above, it is thus seen that the present
invention provides, within an implantable sensor, a means for
automatically verifying the integrity of the sensor on a periodic
basis. This is done, in one emboiment, through the use of
electrical/electronic circuits included as part of the sensor
circuitry which automatically carry out one or more integrity tests
on the sensor on a scheduled basis, and which then eventually
report any out-of-tolerance conditions and/or other problematic or
informational data to appropriate personnel so that needed
corrective action, if any, may be taken.
[0088] While the invention herein disclosed has been described by
means of specific embodiments and applications thereof, numerous
modifications and variations could be made thereto by those skilled
in the art without departing from the scope of the invention set
forth in the claims.
* * * * *